OBJECTIVE: Macrophage migration inhibitory factor (MIF) is a central cytokine in innate immunity. MIF expression can be regulated by glucose and insulin, but data on the association with type 2 diabetes are sparse. The aim of this study was to test whether MIF is associated with impaired glucose tolerance (IGT) and type 2 diabetes and whether these associations are independent of metabolic and immunological risk factors and to compare the associations of MIF and IGT/type 2 diabetes with those of C-reactive protein (CRP) and interleukin-6 (IL-6) with IGT/type 2 diabetes. RESEARCH DESIGN AND METHODS: The Cooperative Health Research in the Region of Augsburg/Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4 (KORA S4) is a population-based survey performed in Southern Germany (1999-2001). Of 1,653 participants aged 55-74 years, 236 patients with type 2 diabetes, 242 subjects with IGT, and 244 normoglycemic control subjects matched for age and sex were included in this cross-sectional study. Serum concentrations of MIF were measured by enzyme-linked immunosorbent assay. RESULTS: Serum MIF concentrations are highly increased in individuals with IGT and type 2 diabetes. The associations of MIF with IGT and type 2 diabetes were independent of classical risk factors and of CRP and IL-6 and were much stronger before and after multivariate adjustment than the associations of CRP and IL-6 with IGT and type 2 diabetes. CONCLUSIONS: Our data suggest that elevations of systemic MIF concentrations precede the onset of type 2 diabetes. This finding may be relevant because MIF has been reported to contribute to the development of type 2 diabetes-related diseases such as atherosclerosis and cancer.